Transcript B cells - regulatoryx

CATEGORY: CELLS
B CELLS: REGULATORY
B Cells: Regulatory (Bregs)
Alistair McIntosh, School of Bioscience,
University of Birmingham, UK
B cells provide innate immunity
Although the positive regulatory role of B has been established for many years, it is now recognised that certain
B-cell lineages can play a role in negatively regulating immune responses, such as reducing inflammation in
autoimmune conditions. When B cells are depleted in animal models, there is an increased manifestation of
autoimmune disease, suggesting certain B-cell lineages regulate inflammation. These B-cell lineages are
referred to as regulatory B cells (Bregs). Various phenotypic variants of cells that appear to negatively
regulate immune responses have been identified, with all the variants sharing the ability to produce IL-10,
which is not secreted by other B cell subsets. IL-10 is a cytokine that inhibits production of pro-inflammatory
cytokines, such as IL-2, IL-3, IFN-γ and TNF-α, and inhibits responses from T-helper type 1 cells (Th1),
suggesting that this cytokine functions as the primary molecule by which Bregs elicit a response. A unique
CD1dhiCD5+CD19hisubset, identified in spleens of naïve wild-type mice, is suggested as the Breg lineage that
contributes to the majority of B cell IL-10 production, once activated by stimulation in vitro. Due to the fact that
this novel B-cell subset only produces IL-10, they have been named B10 cells.
Function of regulatory B cells
Unlike T cells, which respond to antigen following cleavage of peptides, B cells can respond directly to naïve
antigen, due to the presence of the B-cell receptor (BCR). This suggests an earlier involvement of Bregs in an
immune response, when compared to regulatory T cells. However, as a result, the Breg response is also
shorter lived than the regulatory T-cell response.
In humans, Bregs represent a very low proportion of the B-cell population (≈0.5% in healthy individuals).
However there is substantial proof that Bregs are very important B-cell subsets. Treatment of many
autoimmune conditions by B-cell depletion has shown disappointing results. This could be due to depletion of
Bregs, in addition to normal B-cells, removing the protective anti-inflammatory effects provided by the Bregs
and counterbalancing the positive effects from B-cell depletion. When B cells are depleted in mice,
autoimmune diseases can spontaneously develop, providing support for this theory of Breg depletion. As
stated above, these protective properties are derived from production of IL-10. It is believed that IL-10
production is activated upon stimulation of Toll-like receptors (TLRs) in mice, or CD40 and TLRs, in the case
of Humans. The result following activation is the inhibition of cell subsets that are involved in inflammatory
responses, such as T cells or dendritic cells. Bregs can also trigger change in T-cell behaviour via interaction
with T-helper cells. Due to their ability to interact with a vast array of other immune subsets, and inhibit proinflammatory signals, Bregs could be used as a novel therapeutic in autoimmune diseases.
Figure 1. Suggested interactions
between B10 cells and other
immune cells. IL-10 regulates
activation of various immune cellsubsets including dendritic cells (DC),
macrophages, plasma cells (PC), Thelper cells (Th) and B-cells.
© The copyright for this work resides with the author
B lymphocytes (or B cells) are white blood cells that are produced in the bone marrow of mammals.
Traditionally, B cells were thought to predominantly play a role in positively regulating the immune system by
antigen presentation to CD4+, but not CD8+, T cells, which in turn feedback to activate B cells, conferring
humoral immunity. The interaction between B cell and T helper cell is important, as demonstrated by B-cell
deficient or depleted mice having a decreased immune response upon challenge with a pathogen.
CATEGORY: CELLS
B CELLS: REGULATORY
B Cells: Regulatory (Bregs)
cont.
Regulatory B-cell lineage
© The copyright for this work resides with the author
In spite of the evidence for the role of Bregs in the literature, there are still many questions over the origin of
Bregs; IL-10-competent B cells seem to respond to stimulus from the BCR. A reduction in the number of IL-10
competent B cells is seen in mice when CD19, a strong positive regulator of BCR signalling, is knocked out.
Furthermore, preliminary results suggest that both CD40 and lipopolysaccharide (LPS) stimulation promote
production of IL-10 competent B cells. Collectively this suggests that stimulation, mainly in the form of BCR
stimulation, is required for IL-10 competence in B cells. Consequently, the question arises whether Bregs are
found as a unique subset, or are produced from B cells exposed to correct stimuli. In various studies with
mouse models, where B cells with a regulatory role are identified, a unique, consistent phenotype is not
observed between the studies. IL-10-producing B cells have been identified in humans; however variable
results with regards to the identity of the B cell subset responsible for the IL-10 production are also seen, as
with the mouse models. The overall consequence is that the origin, and the overall role, of Bregs in humans
still remains unclear.